Bone is a dynamic tissue that requires physiological or mechanical stimulation to maintain health and function. However, conditions such as microgravity and immobilization prevent bone from being loaded causing a misregulation of bone resorption and bone formation; thus, predisposes the bone to fractures. In the oral cavity, teeth are used to apply load to the jawbone maintaining the bone mineral density and integrity. In edentulous patients, who have complete loss of teeth, the mandibular bone undergoes high level of bone resorption leading to low bone content and increase risk for fractures. The low mineral content complicates dental treatments and healing of the fractured bone. Therefore, it is imperative to understand how mechanical load and lack there of affect bone remodeling. Osteocytes have been implicated to be the mechanosensor in bone with load stimulating osteocyte bone formation activity and unload inducing osteocytes apoptotsis. A notable osteocyte protein is Sclerostin, which represses osteoblast activity by inhibiting the Wnt pathway. Based on our preliminary data, we hypothesize that Sclerostin is regulated by TGF during mechanosensitive bone remodeling. To test this hypothesis, we will define the relationship of TGF, Smad2/3, SOST, and mechanical stimulation in the long bone and the jaw. We will evaluate TGF signaling in a hindlimb loading model, a gain-of-function approach, and TGF response to unloading with a disuse model in the jaw, a loss-of-function approach. We will also use an in vitro system to define the mechanisms that TGF regulate SOST activity. Our proposed research will reveal the regulatory mechanisms used by TGF to modulate Sclerostin for mechanosensitive bone remodeling. Clearer understanding of pathways involved in mechanosensitive bone formation would provide targets for drug development for treating bone loss due to disuse like in edentulism. PUBLIC HEALTH RELEVANCE: One of many consequences of tooth loss is the absence of physical stimulation of the underlying jaw bone by the teeth. Without this stimulation, bone erodes, compromising the success of subsequent dental treatments. This study aims to investigate the molecular details by which bone responds to physical stimulation because this information will provide us with a means to develop treatments for disorders with bone loss, including osteoporosis and tooth loss.